Open AccessCombined effects of two mutations in von Willebrand disease 2M phenotype
Author(s) -
Woods Adriana I.,
Paiva Juvenal,
Kempfer Ana C.,
Primrose Debora M.,
Blanco Alicia N.,
SanchezLuceros Analía,
Lazzari María A.
Publication year - 2018
Publication title -
research and practice in thrombosis and haemostasis
Language(s) - English
Resource type - Journals
ISSN - 2475-0379
DOI - 10.1002/rth2.12067
Subject(s) - von willebrand disease , missense mutation , compound heterozygosity , proband , von willebrand factor , phenotype , medicine , mutation , platelet , heterozygote advantage , coagulopathy , desmopressin , bleeding time , endocrinology , microbiology and biotechnology , genotype , biology , genetics , gene , platelet aggregation
Essentials Compound heterozygosity causes a VWD2M phenotype in a child with severe bleeding symptoms. p.P1648fs*45 changes the folding of A2 domain altering VWF binding to GPIbα and type VI collagen. p.P1648fs*45 was considered as an apparent de novo mutation; AS‐PCR revealed paternal mosaicism. Bleeding score and DDAVP's response were worse than those seen in VWD2M heterozygous controls.Background Type 2M von Willebrand disease (VWD2M) is usually characterized by VWF:RCo/VWF:Ag<0.6 and normal multimeric profile; desmopressin (DDAVP) challenge test commonly shows poor response of VWF:RCo. Objective We describe the bleeding tendency and the laboratory phenotype in a patient carrying two heterozygous mutations affecting VWF ‐A1 domain and VWF ‐A2 domain. Subjects/methods A 12‐year‐old patient (O blood group) with severe hemorrhagic tendency was phenotypically and genotypically analyzed; his parents were also studied. Results The proband showed decrease FVIII:C, VWF:RCo/VWF:Ag, and VWF:CB6/VWF:Ag ratios, but normal platelet count, VWF:CB1/VWF:Ag ratio, VWFpp and multimeric pattern, suggesting a VWD2M phenotype. The DDAVP challenge test, compared to controls (VWD2M patients with mutations in VWF‐A1 domain), showed lower increase of FVIII:C and VWF:Ag than in heterozygous, but very similar to homozygous control. Two mutations were found in heterozygous and trans presentation: p.Pro1648fs*45 and a novel missense mutation, p.Arg1426Cys. The mother was p.Arg1426Cys heterozygous carrier, with few clinical symptoms. The father was asymptomatic, with no mutations. The p.Pro1648fs*45 was considered an apparent de novo mutation; proband's AS‐PCR revealed mosaicism in the paternal allele. According to the predicted models, p.Arg1426Cys would not be affecting the binding of GPIbα to A1 domain, whereas p.Pro1648fs*45 seems to modify the folding of A2 domain, and in this way, it would affect the binding to GPIbα and type VI collagen. We believe that the combination of these two heterozygous mutations, in a child with O blood group, could result in a defective phenotype enhancer.